Kirsten rat sarcoma viral oncogene homolog G12D mutant protein (KRAS G12D)

KRAS G12D mutant protein is a variant of the Kirsten rat sarcoma viral oncogene homolog (KRAS), characterized by a glycine-to-aspartic acid substitution at codon 12. This mutation results in loss of GTPase activity, leading to constitutive activation of the protein and persistent stimulation of downstream signaling pathways controlling cell growth, differentiation, and survival[2][4][5]. The G12D mutation is among the most frequent KRAS mutations found in cancer, particularly in pancreatic, colorectal, and lung cancers[1][2][3]. KRAS is a small GTP-binding protein (GTPase) that acts as a molecular switch in the RAS/MAPK pathway. The G12D mutation locks KRAS in an active, GTP-bound state, driving oncogenic transformation and tumor progression. KRAS G12D is a validated therapeutic target: several small molecules and peptides, such as MRTX1133, KRpep-2d, and the KD2 peptide, have been developed to selectively inhibit this mutant by binding to the switch II pocket (S-II), interfering with essential protein–protein interactions critical for KRAS function and signaling[1][2]. Targeting KRAS G12D presents notable therapeutic challenges, including the high similarity to wild-type KRAS and dynamic conformational flexibility, but it serves as a key disease biomarker and drug target in precision oncology[1][2][3][4].

Other names

KRAS(G12D)K-Ras G12DKRAS Gly12Asp mutantKRAS p.G12DK-Ras (Gly12Asp)KRAS oncogene G12D mutant

Allosteric inhibition of protein–protein interactions at the switch II pocket. Inhibition of GTPase-regulated signaling by direct binding to the mutated form. Selective targeting of the S-II pocket unique to the G12D mutant.